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New directions for biological therapy in rheumatoid arthritis
1Kennedy Institute of Rheumatology, London, UK.
Abstract:
Advances in our understanding of the pathogenesis of rheumatoid arthritis (RA), together with developments in hybridoma and molecular technology have opened the way for more directed therapy in this disease. In reviewing the experience so far with T-cell-directed biological agents, we show that the early promise displayed by anti-CD4 monoclonal antibodies in open clinical trials has not been sustained in controlled studies. This outcome provides a challenge to the concept that CD4+ T cells are of prime importance in RA, and prompts a search for alternative therapeutic targets. Agents directed towards other leucocyte antigens such as CD5, CDw52 or the receptor for interleukin 2 have induced clinical responses in early studies, but at the expense of significant toxicity. Newer therapies targeting the monokines tumour necrosis factor alpha (TNF-alpha), IL-1 and IL-6, and the leucocyte adhesion molecule intercellular adhesion molecule 1 (ICAM-1) have provided encouraging clinical improvements and, in the case of anti-TNF-alpha and anti-IL-6, impressive modulation of the acute-phase response. Strategies allowing long-term blockade of such molecules, including antibody reshaping and the use of soluble cytokine receptors are discussed. Finally, the potential for using biological agents in combination with other therapies is outlined.
Insights
Biological agents targeting T-cells show limited efficacy for rheumatoid arthritis (RA) treatment. Newer therapies targeting cytokines like TNF-alpha and IL-6 offer promising clinical improvements and are discussed for future RA management.
Area of Science:
- Immunology
- Rheumatology
- Pharmacology
Background:
- Rheumatoid arthritis (RA) pathogenesis understanding has advanced.
- Hybridoma and molecular technologies enable targeted therapies for RA.
Purpose of the Study:
- To review the efficacy of T-cell-directed biological agents in RA.
- To explore alternative therapeutic targets and newer biological agents for RA.
Main Methods:
- Review of clinical trial data for anti-CD4 monoclonal antibodies.
- Analysis of early studies on agents targeting CD5, CDw52, and IL-2 receptor.
- Evaluation of newer therapies targeting TNF-alpha, IL-1, IL-6, and ICAM-1.
Main Results:
- Anti-CD4 monoclonal antibodies failed to sustain promise in controlled RA studies.
- Agents targeting other leukocyte antigens showed responses but with significant toxicity.
- Newer therapies targeting monokines and ICAM-1 demonstrated encouraging clinical improvements and modulation of acute-phase response.
Conclusions:
- CD4+ T cells may not be the primary target in RA, necessitating alternative strategies.
- Targeting TNF-alpha and IL-6 shows significant potential for RA treatment.
- Long-term blockade strategies and combination therapies are crucial for future RA management.